Abstract
IT is a general principle of mammalian biochemical genetics that enzymatic activity is proportional to gene dosage; that is, co-dominance of the biochemical phenotype is usual in heterozygotes. A well studied exception is the lethal albino locus of mice. The radiation-induced lethal albino alleles cause prenatal or early neonatal death. The mutations are unusual in their lack of gene dosage effect. Four alleles (c14cos, c112K, c65K, c3H) that are expressed in newborns as absence of pigment, hypoglycaemia, and neonatal death are associated with glucose 6-phosphatase deficiency1,2. Heterozygotes distinguishable by pigment dilution have the same glucose 6-phosphatase levels as normal homozygotes in a number of situations, including enzyme induction with corticoids, glucagon, dibutyryl cyclic AMP, by producing alloxan diabetes, and during normal post-natal development3,4. Four other enzymes (tyrosine aminotransferase, serine dehydratase, bilirubin glucuronyl transferase, and spectrophotometrically-determined cytochrome P-450) that are deficient in lethal albino homozygotes are present in normal levels in heterozygotes (refs 3–5 and M. M. Thaler, R. P. E., and S. Gluecksohn-Waelsch, in preparation). There is evidence that mutation of something other than structural genes for the enzymes is involved. Residual amounts of glucose 6-phosphatase and tyrosine aminotransferase are present in lethal albino homozygotes. Complementation of these lethal albino alleles with two additional lethal albino alleles, c6H and c25H obtained from Harwell, resulted in normal enzyme levels4,5. Also, abnormalities of endoplasmic reticulum of lethal albino hepatocytes are strikingly evident on electron microscopy6. Enzymes deficient in homozygotes are either cyclic AMP-induced or microsomal. A mutation in the gene for a membrane structural protein or in the gene for a component of the cyclic AMP induction system has been suggested as an underlying defect which might account for the deficiency of a number of enzymes and the failure to demonstrate heterozvgote dosage effect, although biochemical and immunological techniques have not yet detected any abnormality (R. P. E., P. Siekevitz, K. Jacobs, and S. Gluecksohn-Waelsch, in preparation).
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DIAMOND, R., ERICKSON, R. Gene dosage in a deletion for a nuclear-coded, mitochondrial enzyme. Nature 248, 418–419 (1974). https://doi.org/10.1038/248418a0
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DOI: https://doi.org/10.1038/248418a0
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